Bottom Line:
The causes underlying glomerular hyperfiltration are not entirely clear.There is evidence from studies in the streptozotocin model of diabetes in rats that an increase of proximal tubular reabsorption results in the withdrawal of a vasoconstrictor input exerted by the tubuloglomerular feedback (TGF) mechanism.We conclude that glomerular hyperfiltration is a primary event in the Akita model of type I diabetes, perhaps driven by an increased filtering surface area, and that it is ameliorated by TGF to the extent that this regulatory system is functional.

ABSTRACTAn increase of glomerular filtration rate (hyperfiltration) is an early functional change associated with type I or type II diabetes mellitus in patients and animal models. The causes underlying glomerular hyperfiltration are not entirely clear. There is evidence from studies in the streptozotocin model of diabetes in rats that an increase of proximal tubular reabsorption results in the withdrawal of a vasoconstrictor input exerted by the tubuloglomerular feedback (TGF) mechanism. In the present study, we have used micropuncture to assess single nephron function in wild type (WT) mice and in two strains of type I diabetic Ins2+/- mice in either a C57Bl/6 (Akita) or an A1AR-/- background (Akita/A1AR-/-) in which TGF is non-functional. Kidney glomerular filtration rate (GFR) of anesthetized mice was increased by 25% in Akita mice and by 52% in Akita/A1AR-/-, but did not differ between genotypes when corrected for kidney weight. Single nephron GFR (SNGFR) measured by end-proximal fluid collections averaged 11.8 ± 1 nl/min (n=17), 13.05 ± 1.1 nl/min (n=23; p=0.27), and 15.4 ± 0.84 nl/min (n=26; p=0.009 compared to WT; p=0.09 compared to Akita) in WT, Akita, and Akita/A1AR-/- mice respectively. Proximal tubular fluid reabsorption was not different between WT and diabetic mice and correlated with SNGFR in all genotypes. We conclude that glomerular hyperfiltration is a primary event in the Akita model of type I diabetes, perhaps driven by an increased filtering surface area, and that it is ameliorated by TGF to the extent that this regulatory system is functional.

Mentions:
Measurements of SNGFR and fluid reabsorption along the proximal tubule by micropuncture confirmed the presence of hyperfiltration at the single nephron level (Figure 1A). Mean SNGFR was 11.8 ± 1 nl/min in WT (n=17), 13.05 ± 1.1 nl/min in Akita (n=23; p=0.27), and 15.4 ± 0.84 nl/min in Akita/A1AR-/- mice (n=26; p=0.009 compared to WT; p=0.09 compared to Akita). The 10.6% and 23% rise of SNGFR in Akita and double mutant mice respectively was less than the 24.8% and 56% increments of whole kidney GFR. Fractional fluid absorptions expressed as the ratio of iothalamate concentration in tubular fluid (TF) over that in plasma (P) (TF/Piothalamate) (Figure 1B) or converted to fractional fluid reabsorption in percent of GFR were not significantly different between WT and diabetic animals, averaging 1.84 ± 0.07 or 44.3 ± 2.3% in WT, 1.72 ± 0.05 or 40.7 ± 1.8% in Akita (p=0.27) and 2.1 ± 0.1 or 49.6 ± 2.3% in Akita/A1AR double mutant mice (p=0.06 compared to WT). Fluid reabsorption in absolute terms (Figure 2A) was not significantly different between WT and diabetic mice, but a tendency for slightly higher SNGFR and TF/Piothalamate values in the Akita/A1AR-/- mice added up to a significantly higher reabsorption rate compared to Akita mice (p<0.05 by ANOVA). Glomerulotubular balance, the relationship between GFR and reabsorption, was not disrupted and was not markedly different in the three strains of mice (Figure 2B).

Mentions:
Measurements of SNGFR and fluid reabsorption along the proximal tubule by micropuncture confirmed the presence of hyperfiltration at the single nephron level (Figure 1A). Mean SNGFR was 11.8 ± 1 nl/min in WT (n=17), 13.05 ± 1.1 nl/min in Akita (n=23; p=0.27), and 15.4 ± 0.84 nl/min in Akita/A1AR-/- mice (n=26; p=0.009 compared to WT; p=0.09 compared to Akita). The 10.6% and 23% rise of SNGFR in Akita and double mutant mice respectively was less than the 24.8% and 56% increments of whole kidney GFR. Fractional fluid absorptions expressed as the ratio of iothalamate concentration in tubular fluid (TF) over that in plasma (P) (TF/Piothalamate) (Figure 1B) or converted to fractional fluid reabsorption in percent of GFR were not significantly different between WT and diabetic animals, averaging 1.84 ± 0.07 or 44.3 ± 2.3% in WT, 1.72 ± 0.05 or 40.7 ± 1.8% in Akita (p=0.27) and 2.1 ± 0.1 or 49.6 ± 2.3% in Akita/A1AR double mutant mice (p=0.06 compared to WT). Fluid reabsorption in absolute terms (Figure 2A) was not significantly different between WT and diabetic mice, but a tendency for slightly higher SNGFR and TF/Piothalamate values in the Akita/A1AR-/- mice added up to a significantly higher reabsorption rate compared to Akita mice (p<0.05 by ANOVA). Glomerulotubular balance, the relationship between GFR and reabsorption, was not disrupted and was not markedly different in the three strains of mice (Figure 2B).

Bottom Line:
The causes underlying glomerular hyperfiltration are not entirely clear.There is evidence from studies in the streptozotocin model of diabetes in rats that an increase of proximal tubular reabsorption results in the withdrawal of a vasoconstrictor input exerted by the tubuloglomerular feedback (TGF) mechanism.We conclude that glomerular hyperfiltration is a primary event in the Akita model of type I diabetes, perhaps driven by an increased filtering surface area, and that it is ameliorated by TGF to the extent that this regulatory system is functional.

ABSTRACTAn increase of glomerular filtration rate (hyperfiltration) is an early functional change associated with type I or type II diabetes mellitus in patients and animal models. The causes underlying glomerular hyperfiltration are not entirely clear. There is evidence from studies in the streptozotocin model of diabetes in rats that an increase of proximal tubular reabsorption results in the withdrawal of a vasoconstrictor input exerted by the tubuloglomerular feedback (TGF) mechanism. In the present study, we have used micropuncture to assess single nephron function in wild type (WT) mice and in two strains of type I diabetic Ins2+/- mice in either a C57Bl/6 (Akita) or an A1AR-/- background (Akita/A1AR-/-) in which TGF is non-functional. Kidney glomerular filtration rate (GFR) of anesthetized mice was increased by 25% in Akita mice and by 52% in Akita/A1AR-/-, but did not differ between genotypes when corrected for kidney weight. Single nephron GFR (SNGFR) measured by end-proximal fluid collections averaged 11.8 ± 1 nl/min (n=17), 13.05 ± 1.1 nl/min (n=23; p=0.27), and 15.4 ± 0.84 nl/min (n=26; p=0.009 compared to WT; p=0.09 compared to Akita) in WT, Akita, and Akita/A1AR-/- mice respectively. Proximal tubular fluid reabsorption was not different between WT and diabetic mice and correlated with SNGFR in all genotypes. We conclude that glomerular hyperfiltration is a primary event in the Akita model of type I diabetes, perhaps driven by an increased filtering surface area, and that it is ameliorated by TGF to the extent that this regulatory system is functional.